Slow inactivation of Vmax in guinea pig ventricular myocardium

Abstract

Measurements of maximum upstroke velocity (Vmax) of guinea pig ventricular action potentials were used to investigate the effect of prolonged depolarization on the inactivation and recovery kinetics of cardiac sodium channels. Membrane potential before stimulated upstrokes was controlled by passing current across a sucrose gap. Two phases of inactivation ("slow" and "ultra-slow") having kinetics and voltage dependence different from the commonly observed fast inactivation process were observed. Ultra-slow inactivation developed exponentially with a time constant of several minutes between -60 and -20 mV. In contrast, slow inactivation developed with a time constant of 1-6 s between -60 and 40 mV. Under steady-state conditions slow and ultra-slow inactivations were virtually absent at -85 mV, while 50% of Vmax underwent slow inactivation at approximately 10 mV and 50% underwent ultra-slow inactivation at approximately -40 mV. Recovery from slow inactivation occurred exponentially with a time constant of about 2 s at -70 to -85 mV and 0.7 s at -100 mV. Recovery from ultra-slow inactivation was not completely characterized but was complete within 20 s at -85 mV. No significant effect of external [K+] (1-10 mM) on slow inactivation was found. The results suggest the existence of two additional inactivated states of the cardiac sodium channel distinctly different from the fast inactivated state.

Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart.

“…Because the change was greater in the longitudinal direction, it seems unlikely that a reduction in cell-to-cell coupling was responsible. 39 The observed change is consistent with sodium channel inactivation, and has a similar time course to the ultraslow sodium current inactivation described by Clarkson et al 33 In the presence of lidocaine, conduction velocity did not drop after the second beat of the rapid train. This suggests that lidocaine inhibits ultraslow sodium current inactivation.…”

“…This suggests that lidocaine inhibits ultraslow sodium current inactivation. 33 Recovery from use-dependent conduction-velocity depression occurred with a time constant of about 120 msec. This is quite similar to the results of others (138 msec,9 152 msec,37 161 msec,38 and 112 msec40).…”

Block of cardiac sodium channels by amiodarone studied by using of action potential in single ventricular myocytes

“…This small P... reduction probably refelcts 'slow inactivation' of cardiac sodium channels (Saikawa & Carmeliet, 1982;Clarkson et at., 1984). (Bean et al, 1982;Cohen et al, 1984;Sheets et al, 1988) Both amiodarone and lignocaine caused only a slight decrease in '.ax of reference action potentials at the concentrations tested (Table 1).…”

Electrophysiological effects of SD‐3212, a new antiarrhythmic agent with vasodilator action, on guinea‐pig ventricular cells

“…In untreated control myocytes, such a clamp pulse with a duration of less than 500 ms had no significant effect on the V.a of the test action potential. However, further prolongation of the clamp pulse duration resulted in a slight but significant Vm1V, reduction probably due to slow inactivation of sodium channels (Saikawa & Carmeliet, 1982;Clarkson et al, 1984). A clamp pulse of 2,000 ms in duration decreased Vma, by 16.6 + 1.6% (n = 4) from the value of action potential without the conditioning clamp (reference level).…”